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Transcription-dependent and -independent signaling of RSK2 in cancer metastasis

癌症转移中 RSK2 的转录依赖性和非依赖性信号传导

基本信息

批准号：
9904525
负责人：
Sumin Kang
金额：
$ 37.05万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904525
关键词：
AMP-activated protein kinase kinase Anoikis Attenuated Bioavailable Biological Biological Process CREB1 gene Cause of Death Cell Death Cells Cessation of life Clinical Clinical Treatment Combined Modality Therapy Complex Data Disseminated Malignant Neoplasm Enzymes Genetic Genetic Transcription Glutamate Dehydrogenase Glutamates Homeostasis Human IRS1 gene In Vitro Link Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolic Pathway Metabolism Modeling Neoplasm Metastasis Oxidation-Reduction Pathway interactions Patients Pattern Pharmacology Phosphorylation Play Process Production Proliferating Property Proteins RPS6KA gene Reporting Research Resistance Ribosomal Protein S6 Kinase Ribosomes Role STK11 gene Series Signal Pathway Signal Transduction Testing Therapeutic Therapeutic Effect Treatment Efficacy Variant anti-cancer attenuation cancer cell cancer type cell type in vivo inhibitor/antagonist knock-down metabolic abnormality assessment metastatic process migration neoplastic cell novel small molecule inhibitor stathmin transcription factor tumor upstream kinase

项目摘要

Metastasis is a complex biological process, which involves multiple signaling pathways. Therefore, a single agent is often insufficient and combination therapy is vitally important in the successful treatment of metastatic cancer. We reported that p90 ribosomal S6 kinase 2 (RSK2) promotes metastasis by activating multiple downstream substrates. In addition, we recently identified that glutamate dehydrogenase 1 (GDH1), a critical enzyme in the glutaminolysis pathway, provides anti-anoikis signals by activating CamKK2 and its downstream AMPK to regulate energy production, protecting cells from anoikis, and promoting metastasis in lung cancer. The effect of GDH1 is evident in LKB1-deficient cancer, where AMPK activation predominantly depends on CamKK2. This suggests that RSK2 and GDH1 are promising anti-metastasis targets. Indeed, targeting RSK2 or GDH1 by fmk (identified by our collaborator Jack Taunton at UCSF) or R162 (identified by our group) attenuated metastasis. We recently found that genetic or pharmacological inhibition of these two distinct signaling axes results in synergistic attenuation of cell invasion, migration, and anoikis resistance in LKB1-deficient lung cancer. Biological and metabolic studies revealed that the combined therapy further attenuates CREB activation. Intriguingly, GDH1 knockdown resulted in decreased activity of CamK4, another upstream kinase of CREB, suggesting that combined targeting of RSK2 and GDH1 may further attenuate CREB activity by inhibiting RSK2 and GDH1-CamKK2-CamK4 signaling involved CREB phosphorylation. In addition, combined targeting of RSK2 and GDH1 synergistically induced anoikis in LKB1 wild-type (wt) expressing cells and RSK2 directly phosphorylated LKB1, leading to AMPK activation. These data suggest that RSK2 may signal through LKB1 and AMPK to contribute to anoikis resistance in LKB1 wt cells. Thus, we hypothesize that RSK2 and GDH1 coordinately regulates AMPK and CREB in transcription- dependent and -independent manners to provide pro-metastatic potential in cancer cells. Thus, targeting both cellular and metabolic signaling by combination of RSK2 and GDH1 inhibitors is a promising anti-metastasis therapeutic strategy. We will use lung cancer with LKB1 or LKB1 null as a research platform. Three specific aims are proposed: (1) To demonstrate whether RSK2 and GDH1 coordinately provides anti-anoikis protection to cancer cells by activating AMPK through LKB1 and CamKK2, respectively; (2) To determine whether RSK2 and GDH1 together mediates migratory and pro-invasive signals by activating CREB and CREB transcription targets; (3) To validate whether RSK2 and GDH1 signaling correlates with metastatic potential in patient tumors and evaluate the therapeutic efficacy of targeting RSK2 and GDH1 in combination in treatment of metastatic cancers.

转移是一个复杂的生物学过程，涉及多种信号通路。因此，单个代理